Hyperactivation of mTORC1 disrupts cellular homeostasis in cerebellar Purkinje cells View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-02-26

AUTHORS

Yusuke Sakai, Hidetoshi Kassai, Hisako Nakayama, Masahiro Fukaya, Tatsuya Maeda, Kazuki Nakao, Kouichi Hashimoto, Hiroyuki Sakagami, Masanobu Kano, Atsu Aiba

ABSTRACT

Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolism. The importance of mTORC1 signaling in neuronal development and functions has been highlighted by its strong relationship with many neurological and neuropsychiatric diseases. Previous studies demonstrated that hyperactivation of mTORC1 in forebrain recapitulates tuberous sclerosis and neurodegeneration. In the mouse cerebellum, Purkinje cell-specific knockout of Tsc1/2 has been implicated in autistic-like behaviors. However, since TSC1/2 activity does not always correlate with clinical manifestations as evident in some cases of tuberous sclerosis, the intriguing possibility is raised that phenotypes observed in Tsc1/2 knockout mice cannot be attributable solely to mTORC1 hyperactivation. Here we generated transgenic mice in which mTORC1 signaling is directly hyperactivated in Purkinje cells. The transgenic mice exhibited impaired synapse elimination of climbing fibers and motor discoordination without affecting social behaviors. Furthermore, mTORC1 hyperactivation induced prominent apoptosis of Purkinje cells, accompanied with dysregulated cellular homeostasis including cell enlargement, increased mitochondrial respiratory activity, and activation of pseudohypoxic response. These findings suggest the different contributions between hyperactivated mTORC1 and Tsc1/2 knockout in social behaviors, and reveal the perturbations of cellular homeostasis by hyperactivated mTORC1 as possible underlying mechanisms of neuronal dysfunctions and death in tuberous sclerosis and neurodegenerative diseases. More... »

PAGES

2799

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-38730-4

DOI

http://dx.doi.org/10.1038/s41598-019-38730-4

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112396018

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30808980


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35 schema:description Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolism. The importance of mTORC1 signaling in neuronal development and functions has been highlighted by its strong relationship with many neurological and neuropsychiatric diseases. Previous studies demonstrated that hyperactivation of mTORC1 in forebrain recapitulates tuberous sclerosis and neurodegeneration. In the mouse cerebellum, Purkinje cell-specific knockout of Tsc1/2 has been implicated in autistic-like behaviors. However, since TSC1/2 activity does not always correlate with clinical manifestations as evident in some cases of tuberous sclerosis, the intriguing possibility is raised that phenotypes observed in Tsc1/2 knockout mice cannot be attributable solely to mTORC1 hyperactivation. Here we generated transgenic mice in which mTORC1 signaling is directly hyperactivated in Purkinje cells. The transgenic mice exhibited impaired synapse elimination of climbing fibers and motor discoordination without affecting social behaviors. Furthermore, mTORC1 hyperactivation induced prominent apoptosis of Purkinje cells, accompanied with dysregulated cellular homeostasis including cell enlargement, increased mitochondrial respiratory activity, and activation of pseudohypoxic response. These findings suggest the different contributions between hyperactivated mTORC1 and Tsc1/2 knockout in social behaviors, and reveal the perturbations of cellular homeostasis by hyperactivated mTORC1 as possible underlying mechanisms of neuronal dysfunctions and death in tuberous sclerosis and neurodegenerative diseases.
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43 Purkinje cells
44 TSC1/2
45 TSC1/2 activity
46 Tsc1/2 knockout
47 Tsc1/2 knockout mice
48 activation
49 activity
50 apoptosis
51 autistic-like behaviors
52 behavior
53 cases
54 cell enlargement
55 cell-specific knockout
56 cells
57 cellular homeostasis
58 cellular metabolism
59 central regulator
60 cerebellar Purkinje cells
61 cerebellum
62 clinical manifestations
63 contribution
64 death
65 development
66 different contributions
67 discoordination
68 disease
69 disrupts cellular homeostasis
70 dysfunction
71 elimination
72 enlargement
73 fibers
74 findings
75 forebrain
76 function
77 homeostasis
78 hyperactivation
79 impaired synapse elimination
80 importance
81 intriguing possibility
82 knockout
83 knockout mice
84 mTORC1
85 mTORC1 disrupts cellular homeostasis
86 mammalian target
87 manifestations
88 mechanism
89 metabolism
90 mice
91 mitochondrial respiratory activity
92 motor discoordination
93 mouse cerebellum
94 neurodegeneration
95 neurodegenerative diseases
96 neuronal development
97 neuronal dysfunction
98 neuropsychiatric diseases
99 perturbations
100 phenotype
101 possibility
102 previous studies
103 prominent apoptosis
104 pseudohypoxic response
105 rapamycin
106 regulator
107 relationship
108 respiratory activity
109 response
110 sclerosis
111 signaling
112 social behavior
113 strong relationship
114 study
115 synapse elimination
116 target
117 transgenic mice
118 tuberous sclerosis
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